Thiuronium compounds as biocidal agents



United States Patent'Ofitice 3,371,010 THIURONIUM COMPOUNDS AS BIOCIDAL AGENTS Pat B. Hamilton, Chapel Hill, N.-C., and Donald R.

Napier, Ponca City, Okla, assignors to Continental Oil Company, Ponca City, Okla., a corporation of Delaware No Drawing. Filed Sept. 29, 1965, Ser. No. 491,432

Claims. (Cl. 167-30) ABSTRACT OF THE DISCLOSURE Improved biocidal agents comprising bis(isothiureidomethyl) alkylaromatic dihydrohalides which have a long chain alkyl group containing at least 10 carbon atoms.

The present invention relates to a class of poly thiuronium compounds which is useful as biocidal agents. More particularly, the present invention relates to improved biocidal agents comprising bis(isothiureidomethyl) alkylaromatic dihydrohalides which have a long chain alkylgroup containing at least 10 carbon atoms.

Inasmuch as thiouronium salts are easily prepared from organic halides and thiourea, and since such compounds are characterized by high crystallinity and narrow melting ranges, they have become well known in the field of qualitative organic analysis. Also, certain thiuronium compounds are known to be efiective as biocidal agents. For example, US. Patent No. 2,999,046 to Rosen teaches a class of thiuronium compounds, similar to those of the present invention, and also teaches that such thiuronium compounds are biologically active. More specifically, he teaches that his thiuronium compounds are useful as parasiticides, insecticides, miticides, and as fungicides. The thiuronium compounds of Rosen are restricted to those containing at most 8 carbon atoms.

In addition, homologous mono thiuronium compounds are known. (US. Patent No. 2,640,079 to De Benneville et al. teaches such a compound.) While the mono thiuronium compounds are effective against gram positive bacteria, it has been our observation that they have only a limited activity against gram negative bacteria.

Unexpectedly, we have found that poly thiuronium compounds derived from alkylaromatic hydrocarbons having at least 10 carbon atoms in the alkyl group give a marked superiority as biocidal agents. More specifically, We have found that poly thiouranium compounds of the type hereinbefore described are superior biocidal agents to similar compounds which (1) have less than 10 carbon atoms in the alkyl group or (2) are the mono homologs.

It is an object of the present invention to provide an improved biocidal agent.

It is another object of the present invention to provide a biocidal agent which is particularly effective against bacteria which are difficult to kill.

It is still another object of the present invention to provide a biocidal agent which is particularly effective in killing gram negative bacteria.

It is a further object of the present invention to provide a method of killing bacteria which comprises subjecting the bacteria to a toxic amount of a poly thiuronium compound as described herein.

Broadly stated, the present invention relates to a composition of matter, having particular utility as a biocidal agent, and having the formula 3,371,010 Patented F eb. 27, 1968 wherein R is an alkyl group containing from 10 to 18 carbon atoms, preferably from 10 to 14 carbon atoms, said alkyl group being either straight or branched chain, wherein A is either hydrogen or a methyl group, wherein X is halogen, which, preferably is chlorine, and wherein n is a number of from about 1.4 to about 2.8, preferably from about 1.6 to about 2.4. (The line is used to indicate that more than one group can be attached.) For convenience, we refer to these compounds as bis thiuronium compounds.

In one aspect the invention relates to a method of killing bacteria which comprises subjecting the bacteria to contact with a toxic amount of a composition as hereinbefore described.

Inasmuch as the alkylaromatic portion of the thiuronium compounds of our invention is an important feature of our invention, this will be described in considerable detail. The aromatic radical of the compounds of our invention is derived from either benzene or toluene, but preferably is derived from benzene. The long chain alkyl group of the alkylaromatic portion of the thiuronium compounds of our invention is either straight or branched chain. Usually, the alkyl group contains from 10 to 18 carbon atoms, but preferably contains from 10 to 14 carbon atoms. In addition, it is to be understood that the thiuronium compounds can be derived from mixtures of alkylaromatic hydrocarbons containing alkyl groups of varying length, as hereinbefore defined. In fact, the commerically available alkylarom-atic hydrocarbons are mixtures.

An example of a particularly suitable commercially available alkylaromatic hydrocarbon which can be used to prepare the biocidal composition of our invention is a material which is known to the trade as dodecylbenzene. Dode'cylbenzene is available under the trade name of Neolene 400 from Continental Oil Company. In a typical process dodecyl'benzene is prepared by first polymerizing propylene to produce a mixture of olefins which are predominantly C (dodecene). Benzene is then alkylated with the dodecene to produce dodecylbenzene. The preparation of dodecylbenzene is described more completely in US. Patent 2,941,015 to Robert R. Kylander, which patent is made a part of this specification. A typical sample of dodecylbenzene 'has the following properties:

Distillation Range, F.

I.B.P. 535 5% 545 10% 550 50% 560 580 97% 592 F.B.P. 603 Recovery, percent 99 Specify gravity, 60 F 0.875 Molecular weight 237 Aniline point 48.5 Bromine No. 0.12 Saybolt color 29 Refractive index, 25 C. 1.4885 Appearance Clear and water White Flash point (closed cup), F. 260 Viscosity, centipoises at 68 F. l4 Viscosity, centipoises at 32 F. 37

It is generally known that the alkyl group in dodecylbenzene is branched chain. More recently, in order to produce detergents which are less resistant to attack by bacteria, straight chain alkylaroma'tic hydocarbons, similar to dodecylbenzene, hape been prepared. These materials constitute a class of materials which, when sulfonated, are known in industry as biodegradable detergents. It is to be understood that any of the n-alkyl-aromatic hydrocarbons which are used in preparing biodegradable detergents and having at least carbon atoms in the alkyl group can be used to prepare the biocidal agents of our invention.

The preparation of a particularly suitable n-alkylaromatic hydrocarbon for use in our invention is described in application Serial No. 129,252, filed August 4, 1961, and having the same assignee as the present application. For reason of convenience, this application is made a part of the present application. Briefly, application Serial No. 129,252 relates to a process of preparing a detergent alkylate wherein the process comprises the following steps, broadly stated: (a) separating a fraction of substantially straight chain C C hydrocarbons from a petroleum distill-ate substantially free of olefins and containing said straight chain hydrocarbons together with non-straight chain hydrocarbons, (b) chlorinating said fraction to the extent whereby between about 10 and about 35 mole percent of the straight chain hydrocarbons present are substantially only mono-chlorinated, (c) alkylating an aromatic compound, selected from the group consisting of benzene, a lower alkyl substituted benzene and mixtures thereof, with the chlorination product of step (b) in the presence of an alkylation catalyst.

n-Alkylaromatic hydrocarbons of the aforementioned type are available under the trademarks Nalkylene 500 and Nalkylene 600 from Continental Oil Company. These materials have the following typical properties:

NALKYLENE" 500 Test Typical Value Test Method Boiling range F.) 535-595 ASTM D447. Bromine Number ASTM D-1158. Average molecular weight Mass spec. Color-Saybolt +25 Specific gravity (/20) 0.850.87 7.. ASTM D-287. Viscosity (Saybolt seconds) 40-45 at 100 F- ASTM 88-44.

NALKYLENE 600 Boiligg range F.):

95 1, 600-615 ASTM 13-447 Bromine Number 0.05 max. P.M. No. 21. Average molecular weight 255-264" Mass spec. Oo1or-Saybolt min P M. No. 20 Specific gravity O.850.87.. ASTM D-287. Viscosity (Saybolt seconds) 40-46 at 100 F. ASTM 88-44.

Still another suitable alkylaromatic hydrocarbon for use in preparing the biocidal composition of our invention is a by-product of the production of a material which we refer to as dimer alkylate. Dimer alkylate has branchedchain alkyl groups, as does dodecyibenzene. Briefly described, dimer alkylate is prepared by the following steps:

(1) di-merization of a suitable feedstock, such as cat poly gasoline, and

(2) alkylation of an aromatic hydrocarbon with the dimer formed in step (1).

Briefly, the dimerization step uses a Friedel-Crafts alkylation sludge as a catalyst. This process is described in application Serial No. 367,417, filed May 14, 1964, and haviiig the same assignee as the present application. The fraction produced by the dimer alkylate process which is suitable for use in preparing the product of this invention is that having a boiling range of about 475 to about 600 F., preferably about 500 to about 590 F., as determined by ASTM procedure D86.

DESCRIPTION OF PROCESS The first step in preparing the biocidal composition of our invention is the preparation of the poly halomethylated alkylaromatic hydrocarbon (preferably bis chloromethylated alkylaromatic hydrocarbon). The preparation of these materials uses a particular chloromethylating agent which is formed by reacting formaldehyde or a compound which engenders formaldehyde with a chlorinecontaining compound which will engender hydrogen chloride in the presence of an alcohol and sulfuric acid.

Suitable chlorine-containing compounds which will engender hydrogen chloride under the conditions used herein include phosphorus trichloride, phosphorus pentachloride, sulfuric oxychloride, sulfurous oxychloride, and acyl chlorides such as acetyl chloride.

Suitable alcohols are the primary monatomic saturated aliphatic alcohols containing from 1 to 4 carbon atoms, such as, for example, methanol, ethanol, normal propanol and normal butanol.

The relative amounts of the various components of the chloromethylating reagent, and the amount of chloromethylating agent used in relation to the alkaryl hydrocarbon, are shown below.

The chloromethylation reaction is conducted at a temperature in the range of about 65 to about C., preferably about 66 to about 68 C., and for a time in the range of from about 2 to about 10 hours, preferably from about 4 to about 6 hours.

Specifically, the chloromethylation procedure can be illustrated as follows: grams of dodecylbenzene is treated with chlorornethylating mixture which has been prepared as follows: 42 grams of p-formaldehyde and 43 grams methyl alcohol are added to a 1-liter Morton flask which is equipped with a sealed stirrer, thermometer, and dropping funnel. The flask is placed in an ice bath and mixing is begun. Phosphorus trichloride (65.5 grams) is added dropwise from the funnel while maintaining a temperature between 29 and 32 C. After the chloride addition, the reaction mass is aged 10 minutes at the same temperature. One hundred seventy-five grams of 100 percent sulfuric acid is then added to the dropping funnel. The sulfuric acid is then added to the reaction mass at a rate to maintain the same temperature. This is followed by post-stirring for an additional 15 minutes. This reaction mass and the dodecylbenzene are combined and heated at 67 C. for 5 hours to produce the chloromethylated dodecylbenzene.

It should be noted that usually the halomethylatiou products are mixtures of homologous products containing 1, 2 or 3 halomethyl groups. Moreover, the distribution: of these products varies according to the type of alkylaromatic hydrocarbon employed. Thus, while the above-- identified Neolene 400 and Nalkylene 500 exhibit: approximately equal reactivity in a dihalomethylation" process, the product of the former is essentially all bisderivative, whereas the product of the latter is more nearly" a mixture of mono and tris derivatives.

The degree of halomethylation is the average of the: number of halomethyl groups present. As indicated pre-- viously, for reason of convenience we refer to those compounds derived from materials having from about 1.4 to about 2.8 halomethyl groups, preferably from about 1.6 to about 2.4 halomethyl groups, as bis compounds.

The second step in the process of preparing the biocidal agents of our invention comprises reacting the bis-halomethylated alkylaromatic hydrocarbon with thiourea. The reaction is generally carried out in the presence of an inert volatile organic solvent (e.g., isopropanol). Since the reaction of the second step is well known to those skilled in the art, it is believed that further description is unnecessary.

In order to disclose the nature of the present invention still more clearly, the following illustrative examples will be given. It is to be understood that the invention is not to be limited to the specific conditions or details set forth in these examples except in so far as such limitations are specified in the appended claims.

EXAMPLE 1 Nalkylene 500 and chloromethylating reagent (3.4 equivalents) prepared as outlined above were combined and heated hours at 6768 C. The crude product was separated, washed with water, dilute base and subsequently dried. Analysis of the finished product indicated at 94.5 percent yield of chloromethylated alkylbenzene containing 17.1 weight percent chlorine and having an average of 1.6 chloromethyl groups per molecule. The product was a mixture consisting essentially of mono, his and tris halomethyl alkylbenzene together with minor amounts of diarylmethane-type condensation products.

EXAMPLE 2 Dodecylbenzylchloride derived from propylene tetramer was treated 3 hours at 75 C. with 3.4 equivalents of the abovedescribed chloromethylating reagent. After separation, the crude product was subjected to a further identical chloromethylation. Distillation of the second product yielded a 91/9 mixture of bis and mono chloromethyldodecylbenzene (boiling range: l50l70 C./0.1 mm.) obtained as a viscous water-white liquid.

Refiuxing 3 hours a solution of 91/9 bis-mono chloride, thiourea percent excess) and isopropanol (1 part) produced the corresponding isothiuronium salts in essentially quantitative yield.

EXAMPLE 3 This example illustrates that the his thiuronium compounds are more effective than the mono thiuronium compounds as bactericidal agents.

The hydrocarbon used was dodecylbenzene (branched chain C -C predominantly C This material was chloromethylated using the procedure described herein to produce a product containing 10 mole percent bis(chloromcthyl)dodecylbenzene. This product was then fractionally distilled to give mono-bis(chloromethyl) dodecylbenzene mixtures with his contents ranging from 2.5 percent to 91 percent. These products were converted to the corresponding thiuronium chlorides by heating with thiourea (5 percent excess) in 1 part isopropanol. Tests against two gram negative organisms, Pseudomonas aeruginosa and Escherichia coli, were made with five of the thiuronium preparations. The minimum inhibitory concentrations of the preparations were determined in an arithmetic dilution assay, the technique of which is Well known to those versed in the art. The test medium was nutrient broth which had received a 0.1 percent inoculum of a 6-hour old culture in Difco AC Broth which had been incubated at 37 C. The assay was read after incubation at 37 C. for 42 hours. An analysis of variance was performed on the data to obtain 95 percent confidence limits.

The results obtained Were as follows:

Minimum Inhibitory Cone. (p.p.m.)

Bis/mono mole ratio E. colt (g. P. aeruginoxa (g.-)

12;];1. 7 1 47 7. 43:0. 3 47 5. OiO. 4 31:1:0. 9 4.010. 4 9. 7i0. 5 2. 05:0. 2 53:0. 5

! Approximate maximum solubility in medium.

bacterial agents, was due primarily to the bis thiuronium compound.

EXAMPLE 4 This example illustrates the superior bactericidal effects of the compounds of our invention as compared to similar materials.

The compounds of our invention which were tested had the following formulas Compound C C12 2s C 2N(CHa)a *From propylene tetramer. contained 91 percent bis.

Compound D NH OHzSC\ 'HCI CHzN(CHa)3CI *From propylene tetramer.

Compound E 12E125 CH2N(OHa)a *From propylene tetramez.

Using the arithmetic dilution technique described in Example 3, the following results were obtained.

Compounds A B o D E Bacteria Minimum Inhibitory Concentration, p.p.1n.

B. cerus (g.+) 2 2 16 3 2 S. aureus (g.+) 2 1 4 1 1 P. fluorescens (g.-) 5 16 47 33 37 P. aeruginosa (g.) 5 10 47 28 28 E. colt (g.) 2 2 23 6 12 s. typltosa (g. 2 2 1e 5 s P. vulgaris (g.) 3 3 3 7 7 EXAMPLE 5 This example illustrates the superior bactericidal prop erties of the compositions of our invention as compared to the compounds suggested by Rosen. The compounds tested had the following formulas (A material suggested by Rosen.)

Using the arithmetic dilution technique described in Example 3, the following results were obtained:

CsHn l NI-Iz 1.0

Amount of Compound F Compound G Compound H Compound (p.p.m.) P. f. S. a. P. f. S. a. P. f. S. a.

+= Growth at indicated concentration of compound. =No growth.

P. J.=Pseudomonas fluorescem.

S. a.=Staphlococcus aureus.

The above data shows that the C compound of our invention is at least 50 fold better than the C compound suggested by Rosen. It also shows that the C compound is superior to the C compound in controlling the gram negative organism Pseudomonas fluorescens by a factor of about 5 to 1. It is well known to those skilled in the art that gram negative organisms and particularly pseudomonads are highly resistant to most antimicrobial agents. Hence, the improvement shown by the compound of our invention is highly significant.

While particular embodiments of the invention have been described, it will be understood, of course, that the invention is not limited thereto, since many modifications may be made; and it is, therefore, contemplated to cover by the appended claims any such modifications as fall within the true spirit and scope of the invention.

The invention having been described, what is claimed and desired to be secured by Letters Patent is:

- 1. A composition of matter, suitable for use as a biocidal agent, having the formula wherein R is an alkyl group containing from 10 to 20 carbon atoms and which is straight or branched chain, A is either hydrogen or a methyl group, X is a halogen, and n is a number of from about 1.4 to about 2.8.

2. A composition of matter as described in claim 1 characterized further in that X is chlorine.

3. A composition of matter as described in claim 2 characterized further in that R is an alkyl group containing from 10 to 14 carbon atoms.

4. A composition of matter as described in claim 3 characterized further in that n is a number of from about 1.6 to about 2.4.

5. A composition of matter, suitable for use as a biocidal agent, having the formula NH a R WCHQSC -HC1 wherein R is an alkyl group containing from 10 to 14 carbon atoms and n is a number of from about 1.6 to about 2.8.

6. A composition of matter, suitable for use as a biocidal agent, having the formula wherein n is a number of from about 1.4 to about 2.8, X is a halogen, and the multivalent radical is derived from dodecylbenzene produced by the polymerization of propylene.

7. A method of killing bacteria which comprises subjecting the bacteria to contact with a tonic amount of a composition of matter having the formula wherein R is an alkyl group containing from 10 to 20 carbon atoms and which is straight or branched chain, A is either hydrogen or a methyl group, X is a halogen, and n is a number ranging from about 1.4 to about 2.8.

8. A method of killing bacteria as described in claim 7 characterized further in that X is chlorine.

9. A method of killing bacteria as described in claim 8 characterized further in that R is an alkyl group containing from 10 to 14 carbon atoms.

10. A method of killing bacteria as described in claim 9 characterized further in that n is a number of from about 1.6 to about 2.4.

References Cited UNITED STATES PATENTS 5/1953 de Benneville et al. 260564 9/1961 Rosen 167-30 

